Nearly one million people die every year from bacterial infections that cannot be treated with common antibiotics.

At this stage this is not the "slate wiper" as that figure represents just four days worth of world wide population growth, but it these continue to spread and other diseases become multi- or pan- resistance then these could rival a flu pandemic in the damage done (even if it is over a longer period).

Date: September 3, 2018Source: University of California - Los AngelesSummary: Biologists have identified more than 8,00 new combinations of antibiotics that are surprisingly effective. 'We expect several of these combinations, or more, will work much better than existing antibiotics,' said one of the researchers, a professor of ecology and evolutionary biology.

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Scientists have traditionally believed that combining more than two drugs to fight harmful bacteria would yield diminishing returns. The prevailing theory is that that the incremental benefits of combining three or more drugs would be too small to matter, or that the interactions among the drugs would cause their benefits to cancel one another out.

Now, a team of UCLA biologists has discovered thousands of four- and five-drug combinations of antibiotics that are more effective at killing harmful bacteria than the prevailing views suggested. Their findings, reported today in the journal npj Systems Biology and Applications, could be a major step toward protecting public health at a time when pathogens and common infections are increasingly becoming resistant to antibiotics.

"There is a tradition of using just one drug, maybe two," said Pamela Yeh, one of the study's senior authors and a UCLA assistant professor of ecology and evolutionary biology. "We're offering an alternative that looks very promising. We shouldn't limit ourselves to just single drugs or two-drug combinations in our medical toolbox. We expect several of these combinations, or more, will work much better than existing antibiotics."

Working with eight antibiotics, the researchers analyzed how every possible four- and five-drug combination, including many with varying dosages -- a total of 18,278 combinations in all -- worked against E. coli. They expected that some of the combinations would be very effective at killing the bacteria, but they were startled by how many potent combinations they discovered.

For every combination they tested, the researchers first predicted how effective they thought it would be in stopping the growth of E. coli. Among the four-drug combinations, there were 1,676 groupings that performed better than they expected. Among the five-drug combinations, 6,443 groupings were more effective than expected.

"I was blown away by how many effective combinations there are as we increased the number of drugs," said Van Savage, the study's other senior author and a UCLA professor of ecology and evolutionary biology and of biomathematics. "People may think they know how drug combinations will interact, but they really don't."

On the other hand, 2,331 four-drug combinations and 5,199 five-drug combinations were less effective than the researchers expected they would be, said Elif Tekin, the study's lead author, who was a UCLA postdoctoral scholar during the research.

Some of the four- and five-drug combinations were effective at least partly because individual medications have different mechanisms for targeting E. coli. The eight tested by the UCLA researchers work in six unique ways.

"Some drugs attack the cell walls, others attack the DNA inside," Savage said. "It's like attacking a castle or fortress. Combining different methods of attacking may be more effective than just a single approach."

Said Yeh: "A whole can be much more, or much less, than the sum of its parts, as we often see with a baseball or basketball team." (As an example, she cited the decisive upset victory in the 2004 NBA championship of the Detroit Pistons -- a cohesive team with no superstars -- over a Los Angeles Lakers team with future Hall of Famers Kobe Bryant, Shaquille O'Neal, Karl Malone and Gary Payton.)

Yeh added that although the results are very promising, the drug combinations have been tested in only a laboratory setting and likely are at least years away from being evaluated as possible treatments for people.

"With the specter of antibiotic resistance threatening to turn back health care to the pre-antibiotic era, the ability to more judiciously use combinations of existing antibiotics that singly are losing potency is welcome," said Michael Kurilla, director of the Division of Clinical Innovation at the National Institutes of Health/National Center for Advancing Translational Science. "This work will accelerate the testing in humans of promising antibiotic combinations for bacterial infections that we are ill-equipped to deal with today."

The researchers are creating open-access software based on their work that they plan to make available to other scientists next year. The software will enable other researchers to analyze the different combinations of antibiotics studied by the UCLA biologists, and to input data from their own tests of drug combinations.

Using a MAGIC framework

One component of the software is a mathematical formula for analyzing how multiple factors interact, which the UCLA scientists developed as part of their research. They call the framework "mathematical analysis for general interactions of components," or MAGIC.

"We think MAGIC is a generalizable tool that can be applied to other diseases -- including cancers -- and in many other areas with three or more interacting components, to better understand how a complex system works," Tekin said.

Savage said he plans to use concepts from that framework in his ongoing research on how temperature, rain, light and other factors affect the Amazon rainforests.

He, Yeh and Mirta Galesic, a professor of human social dynamics at the Santa Fe Institute, also are using MAGIC in a study of how people's formation of ideas is influenced by their parents, friends, schools, media and other institutions -- and how those factors interact.

Other co-authors of the new study are Cynthia White, a UCLA graduate who was a research technician while working on the project; Tina Kang, a UCLA doctoral student; Nina Singh, a student at the University of Southern California; Mauricio Cruz-Loya, a UCLA doctoral student; and Robert Damoiseaux, professor of molecular and medical pharmacology, and director of UCLA's Molecular Screening Shared Resource, a facility with advanced robotics technology where Tekin, White, and Kang conducted much of the research.

The research team reported in 2016 that combinations of three antibiotics can often overcome bacteria's resistance to antibiotics, even when none of the three antibiotics on its own -- or even two of the three together -- is effective. The biologists reported in 2017 two combinations of drugs that are unexpectedly successful in reducing the growth of E. coli bacteria.

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Materials provided by University of California - Los Angeles. Note: Content may be edited for style and length.

33,000 people die every year due to infections with antibiotic-resistant bacteria

Date: November 6, 2018Source: European Centre for Disease Prevention and Control (ECDC)Summary: An new study estimates the burden of five types of infections caused by antibiotic-resistant bacteria of public health concern in the European Union and in the European Economic Area (EU/EEA). The burden of disease is measured in number of cases, attributable deaths and disability-adjusted life years (DALYs). These estimates are based on data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) data from 2015. Share:

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An ECDC study estimates the burden of five types of infections caused by antibiotic-resistant bacteria of public health concern in the European Union and in the European Economic Area (EU/EEA). The burden of disease is measured in number of cases, attributable deaths and disability-adjusted life years (DALYs). These estimates are based on data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) data from 2015.

The authors said "the estimated burden of infections with antibiotic-resistant bacteria in the EU/EEA is substantial compared to that of other infectious diseases, and increased since 2007. Strategies to prevent and control antibiotic-resistant bacteria require coordination at EU/EEA and global level. However, our study showed that the contribution of various antibiotic-resistant bacteria to the overall burden varies greatly between countries, thus highlighting the need for prevention and control strategies tailored to the need of each EU/EEA country."

The study estimates that about 33000 people die each year as a direct consequence of an infection due to bacteria resistant to antibiotics and that the burden of these infections is comparable to that of influenza, tuberculosis and HIV/AIDS combined. It also explains that 75% of the burden of disease is due to healthcare-associated infections (HAIs) and that reducing this through adequate infection prevention and control measures, as well as antibiotic stewardship, could be an achievable goal in healthcare settings.

Finally, the study shows that 39% of the burden is caused by infections with bacteria resistant to last-line antibiotics such as carbapenems and colistin. This is an increase from 2007 and is worrying because these antibiotics are the last treatment options available. When these are no longer effective, it is extremely difficult or, in many cases, impossible to treat infections.

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European Centre for Disease Prevention and Control (ECDC). "33,000 people die every year due to infections with antibiotic-resistant bacteria." ScienceDaily. ScienceDaily, 6 November 2018. <www.sciencedaily.com/releases/2018/11/181106104213.htm>.

Drug-resistant superbug quietly spreading through world's hospitals: studyHospitalAn empty hospital bed is seen in an undated file photo. (The Canadian Press Images/Bayne Stanley)

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AFP Published Monday, September 3, 2018 2:32PM EDT A superbug resistant to all known antibiotics that can cause severe infections or even death is spreading undetected through hospital wards across the world, scientists in Australia warned on Monday.

Researchers at the University of Melbourne discovered three variants of the multidrug-resistant bug in samples from 10 countries, including strains in Europe that cannot be reliably tamed by any drug currently on the market.

"We started with samples in Australia but did a global snapshot and found that it's in many countries and many institutions around the world," Ben Howden, director of the university's Microbiological Diagnostic Unit Public Health Laboratory told AFP.

"It seems to have spread."

The bacteria, known as Staphylococcus epidermidis, is related to the better-known and more deadly MRSA.

It's found naturally on human skin and most commonly infects the elderly or patients who have had prosthetic materials implanted, such as catheters and joint replacements.

"It can be deadly, but it's usually in patients who already are very sick in hospital... it can be quite hard to eradicate and the infections can be severe," Howden said.

His team looked at hundreds of S. epidermidis specimens from 78 hospitals worldwide.

They found that some strains of the bug made a small change in its DNA that led to resistance to two of the most common antibiotics, often administered in tandem to treat hospital infections.

"These two antibiotics are unrelated and you would not expect one mutation to cause both antibiotics to fail," said Jean Lee, a PhD student at Melbourne's Doherty Institute, and co-author of the study.

Many of the most powerful antibiotics are extremely expensive and even toxic, and the team behind the study said that the practice of using multiple drugs at once to prevent resistance may not be working.

'Biggest danger'

The researchers said they believe the superbug is spreading rapidly due to the particularly high use of antibiotics in intensive care units, where patients are sickest and strong drugs are prescribed as routine.

The World Health Organization has long warned of antibiotic overuse sparking new strains of killer, drug-resistant bacteria.

Another Australian study, published last month, suggested some hospital superbugs are growing increasingly tolerant to alcohol-based disinfectants found in handwashes and sanitisers used on hospital wards.

Howden said his study, published in the journal Nature Microbiology, showed the need for better understanding of how infections spread and which bacteria hospitals choose to target.

"This highlights that the use of more and more antibiotics is driving more drug-resistant bacteria," he said.

"With all bacteria in a hospital environment we are driving more resistant strains and there's no doubt that antibiotic resistance is one of the biggest dangers to hospital care worldwide."

'Simple modification' could help antibiotics overcome resistancePublished Tuesday 6 November 2018By Catharine Paddock PhD Fact checked by Jasmin Collier Scientists have developed a simple way of altering antibiotics that could make them much more powerful against infections caused by drug-resistant microbes.

A simple chemical modification could boost antibiotics' effectiveness in the fight against microbial resistance.

The method made the antibiotic vancomycin much more powerful against two strains of bacteria that had become drug-resistant.

The researchers suggest that the simple chemistry involved in modifying the drug can be applied to other antibiotics and even to anticancer drugs.

A paper on the "bioconjugation technique" now features in the journal Nature Chemistry.

"Typically," says senior study author Bradley L. Pentelute, who is an associate professor of chemistry at Massachusetts Institute of Technology (MIT) in Cambridge, "a lot of steps would be needed to get vancomycin in a form that would allow you to attach it to something else, but we don't have to do anything to the drug."

He goes on to explain that they mixed the drug with an antimicrobial peptide and got a "conjugation reaction."

He and others at MIT worked on the study with colleagues from Yale University in New Haven, CT, and the biotech company Visterra, which is also based in Cambridge, MA.Antibiotic resistance

Antibiotic resistance develops because every time someone uses an antibiotic drug, a small population of naturally resistant microbes survives. Resistance spreads not only because the resistant germs predominate, but also because they share their resistance with other microbes.

A global review published in 2016 suggested that around 10 million lives per year could be at risk due to increasing antimicrobial resistance.

Scientists suggest that the leaf ecosystem of a common weed could yield new drugs after finding a new type of antibiotic there.Read now

Without effective antibiotics, many medical procedures — including cesarean delivery, bowel surgery, chemotherapy, and joint replacement — could pose such a high risk of infection that they "become too dangerous" to carry out.

Every year in the United States, antibiotic-resistant germs infect around 2 million people and are responsible for around 23,000 deaths, according to the Centers for Disease Control and Prevention (CDC).

Infections due to germs that have become resistant to antibiotics are very difficult, and in some cases impossible, to treat. Alternative treatments tend to cost more and have worse side effects.

People with these infections often have to stay in the hospital longer and need more visits from the doctor.'Handle' for attaching small proteins

The chemistry of the new method came from a previous discovery that the amino acid selenocysteine can act as a "handle" for attaching small-molecule drugs, such as vancomycin, to small proteins called antimicrobial peptides, which form part of the immune defenses of most organisms.

When they used the method to attach the peptides to vancomycin, the scientists found that they consistently attached to the same place on the antibiotic, producing molecules that were chemically identical.

Existing approaches to making such molecules would not be able to achieve such purity and would need more than a dozen steps to prepare vancomycin for attaching to peptides, note the researchers.

They tested several "conjugates" of vancomycin paired with various different antimicrobial peptides, including one called dermaseptin.

The tests showed that combining vancomycin with dermaseptin made the antibiotic five times more potent against the infectious bacterium Enterococcus faecalis.

E. faecalis is a strain of Enterococcus, a genus of bacteria that has emerged as an important cause of infection in healthcare settings. Urinary tract infections are the most common types of infection that these bacteria cause, and the "rapid rise" of their resistance to vancomycin has been a particular worry to medical professionals.'Valuable technique for the community'

In addition, the team found that vancomycin combined with another antimicrobial peptide called RP-1 killed Acinetobacter baumannii, against which vancomycin alone has no effect. A. baumannii is also highly drug-resistant and a frequent cause of healthcare-associated infections.

Tests with around 30 other molecules, including resveratrol and serotonin, suggest that the approach can easily link peptides to practically any organic molecule that has the "right kind of electron-rich ring," note the researchers.

However, they point out that they did not test the safety of the modified drugs.

They suggest that their method could also apply to other types of drug; for example, to attach antibodies to anticancer drugs so that they reach particular targets without harming healthy tissue.

The authors conclude:

"Given these results, we believe our chemistry will be a valuable bioconjugation technique for the community and may lead to the generation of therapeutic conjugate molecules."

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